This program project aims to improve understanding of the pathogenesis and treatment of autonomic failure. To achieve this goal, a series of closely integrated, highly focussed projects are proposed. We will compare the restricted autonomic neuropathy of the postural tachycardia syndrome (POTS) with the severe generalized autonomic disorders (multiple system atrophy [MSA], pure autonomic failure [PAF], and the autonomic neuropathies) to define the natural history, pathogenetic mechanisms, and treatment strategies (Project 1: Low). These goals are uniquely achievable at Mayo since we have a large cohort of patients with POTS and generalized autonomic failure whose disorders have been well characterized using quantitative tests of known sensitivity and specificity. Closely integrated with Project 1 is Project 3 (Joyner), which will use microneurographic techniques to directly measure sympathetic traffic to skeletal muscle in POTS and vasovagal syncope and directly measure venous and arterial pressures in response to graded lower body negative pressure (to apportion the rules of cardiopulmonary and arterial baroreceptors). This project will also test the novel hypothesis that vasovagal syncope is due to active vasodilatation, mediated by nitric oxide. We will test the hypothesis that autonomic failure is MSA is significantly due to a depletion of medullary catecholamine- and neuropeptide-containing neurons known to be involved in visceral control. Immunocytochemical labeling of tyrosine hydroxylase (TH), neuropeptide Y (NPY), and substance P (sP), and histochemical reaction of nitric oxide synthase containing neurons will be used for the morphometric studies (Project 2: Benarroch). Finally, we have, for the first time, reliable models of preganglionic and postganglionic autonomic failure. By applying similar pharmacologic and morphometric techniques and questions to the human and experimentally models, we are uniquely situated to relate and evaluate postulated mechanisms in MSA and PAF (Projects 1-3) with these models (Project 4: Brimijoin). Taken together, this program will seriously begin to address a major public health problem of autonomic failure.